Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H2S) is the third gaseous mediator in mammals. H2S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5′-phosphate (vitamin B6) as a cofactor.
It is believed that H2S stimulates ATP-sensitive potassium channels (KATP) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H2S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also attenuating their physiological functions, like nitric oxide does.
Recent studies have shown that H2S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H2S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. It is believed that exogenous H2S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs.
More particularly, it has recently been observed that H2S exerts anti-inflammatory and analgesic activities. H2S is an endogenous substance, produced in many tissues and affecting many functions (Wang, Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 2002; 16: 1792-1798). It has also been shown to be a vasodilator and can suppress leukocyte adherence to the vascular endothelium (Wang, 2002; Fiorucci et al., Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology. 2005; 129: 1210-1224). Further, Fiorucci et al. (2005) have demonstrated that pretreatment with an H2S donor can diminish the severity of NSAID-induced gastric damage in the rat.
It is believed that the production of endogenous H2S is altered in many diseases. Furthermore, the levels of H2S may be effected by currently used drugs. For example, acetylsalic acid and non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to have an inhibitory effect on the CSE-H2S pathway in gastrointestinal mucosa (Fiorucci, S. et al). This effect may contribute to gastric mucosal injury induced by these drugs. Thus, pharmacological modulation of H2S levels could be of potential therapeutic value.
It is also thought that H2S may have a role in cardiovascular pathology and, as such, its level should be examined in patients with various risk factors of atherosclerosis such as arterial hypertension, hyperlipidemia, diabetes mellitus, etc. Given that H2S is quenched by reactive oxygen species (ROS) (Whiteman, M. et al., The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrate ‘scavenger’?, J. Neurochem. 2004; 90: 765-768), and considering the important role of oxidative stress in many diseases such as atherosclerosis, arterial hypertension, Alzheimer's disease, etc., it is thought that excessive ROS production may cause H2S deficiency.
Beta-blockers, which used for angina, hypertension and cardiac arrhythmia treatment, show respiratory side effects such as dyspnoea, bronchoconstriction, etc., and therefore may cause problems in patients affected by asthma, bronchitis, and the like. Therefore, beta-blockers further worsen respiratory diseases such as asthma. Hence, in asthmatic patients doses of said drugs must be used reduced in order not to jeopardize even more the respiratory functionality. Thus the efficacy of the beta-blockers is reduced.
Antithrombotics, such as for example dipyridamole, aspirin, etc., used for the prophylaxis of thrombotic phenomena, have a number of side effects such as stomach pain, nausea and other gastrointestinal tract complications. In patients affected by pathologies connected to oxidative stress, the therapeutic action or the tolerability of these drugs, as in the case of aspirin, is greatly reduced.
Bronchodilators, for example, salbutamol, etc., are used in the treatment of asthma and bronchitis and drugs active on the cholinergic system are used in pathologies such as urinary incontinence. Their administration can produce side effects affecting the patient's cardiovascular system, causing problems both to cardiopathic and to hypertensive patients.
Expectorant and mucolytic drugs, which are used in the therapy of inflammatory states of the respiratory organs, can give rise to heartburn and gastric irritability, particularly in the elderly.
Bone resorption inhibitors, such as diphosphonates (for example alendronate, etc.) are drugs showing high gastrointestinal toxicity.
Phosphodiesterase inhibitors, such as, for example, sildenafil, zaprinast, used in the treatment of cardiovascular and respiratory system diseases, are characterized by similar problems as to tolerability and/or efficacy, in particular, in pathological conditions of oxidative stress.
Antiallergic drugs, for example, cetirizine, montelukast, etc. show similar problems in the mentioned pathological conditions, particularly with respect to their efficacy.
Anti-angiotensin drugs such as ACE-inhibitors, for example, enalapril, captopril, etc., and receptor inhibitors, for example, losartan, etc., are used in the cardiovascular disease treatment. These drugs may produce respiratory side effects (i.e., cough, etc.), in particular, in pathological conditions of oxidative stress.
Antidiabetic drugs, both of the insulin-sensitizing and of hypoglycaemizing type, such as for example sulphonylureas, tolbutamide, glypiride, glyclazide, glyburide, nicotinamide etc., are ineffective in the prophylaxis of diabetic complications. Their administration can give side effects, such as, for example, gastric lesions. These phenomena become more intense in pathological conditions of oxidative stress.
Antibiotics, for example, ampicillin, clarihtromycin, etc., and antiviral drugs, for example, acyclovir, etc., show problems as regards their tolerability, for example they cause gastro-intestinal irritability.
Antitumoral drugs, for example, doxorubicine, daunorubicin, cisplatinum, etc., have high toxicity, in a number of organs, among which are the stomach and intestines Said toxicity is further worsened in the above mentioned pathologies of oxidative stress.
Antidementia drugs, for example, nicotine and colinomimetics, are characterized by a poor tolerability especially in pathological conditions of oxidative stress.
Thus, there is a need to have available drugs showing an improved therapeutic performance, i.e., having a lower toxicity and/or higher efficacy, so that they could be administered to patients in morbid conditions of oxidative stress and/or endothelial dysfunctions, without showing the drawbacks of the drugs of the prior art.
Surprisingly, the present inventors have discovered that 4-hydroxythiobenzamide (also referred to herein as 4-HTB or TBZ) is an effective H2S releasing moiety in tissues and when either covalently linked to a drug or it forms a salt with a drug, drug derivatives are formed have reduced side effects. For example, the drug derivatives of the present invention produce significantly less gastrointestinal and/or cardiovascular side effects.